A. Field of the Invention
The present invention relates to compounds and pharmaceutical compositions which inhibit lipoxygenase and are useful as anti-inflammatory and anti-allergy agents.
It is well recognized that arachidonic acid, an essential unsaturated fatty acid, is enzymatically oxygenated to various products, including, prostaglandins, thromboxanes, the 5-, 11-, 12- and 15-hydroxyeicosatetraenoic acids (HETEs, DIHETEs, TRIHETEs) and hydroperoxyeicosatetraenoic acids (HPETEs) and the leukotrienes, all of which have potent physiological effects. The leukotrienes, which are produced via the 5-lipoxygenase pathway, are the major contributors to the onset of the symptoms of asthma, and are mediators for immediate hypersensitivity reactions and inflammation.
Leukotrienes are found in inflammatory exudates and are involved in the process of cellular invasion during inflammation. The term "leukotrienes" is used as a generic term to describe a class of substances, such as slow-reacting substance (SRS) which is an important mediator in asthma and other immediate hypersensitivity reactions. Immunologically generated SRS is usually referred to as slow-reacting substance of anaphylaxis (SRS-A). SRS-A consists of leukotrienes (LT) known as A.sub.4, B.sub.4, C.sub.4, D.sub.4, and E.sub.4. LTC.sub.4 is at least 100 times more potent than histamine in causing long lasting bronchoconstricting effects. The leukotrienes also increase vascular permeability and cause decreased cardiac output and impaired ventricular contraction. LTB.sub.4 may be an important mediator of inflammation in inflammatory bowel disease.
Chemotaxis is a reaction by which the direction of migration of cells is determined by substances in their environment. It is one of the major processes bringing leukocytes from the blood to an inflammatory site, whether the inflammation is caused by an infectious agent, allergic challenge, or other pro-inflammatory stimuli. LTB.sub.4 is not only chemotactic for neutrophils and monocytes, but is also highly active in stimulating eosinophil locomotion. The infiltration of eosinophils is one of the histologic features of a variety of allergic reactions. LTB.sub.4 also stimulates calcium influx and aggregation of polymorphonuclear leukocytes and LTB.sub.4 may, thus, play an important role in mediating both acute and chronic inflammation.
Rheumatoid spondylitis is characterized by an acute neutrophil flare in the joint which is associated with elevated levels of LTB.sub.4. LTB.sub.4 is also present in gouty effusions; and exposure to urate crystals is known to stimulate LTB.sub.4 production by neutrophils. Accordingly, the 5-lipoxygenase inhibitors of the present invention through inhibition of neutrophil attraction and activation in arthritic joints should reduce the protease and oxidative burden believed responsible for joint destruction in arthritic diseases.
With the exception of benoxaprofen which has 5-lipoxygenase activity, aspirin and the other non-steroidal anti-inflammatory agents (NSAIDs) such as indomethacin, ibuprofen, fenoprofen, and the like, inhibit the synthesis of prostaglandins via the cyclooxygenase pathway of arachidonic acid metabolism. These prostaglandin synthetase inhibitors generally exhibit anti-inflammatory, anti-pyretic and analgesic activity, and are widely used in the treatment of arthritis. The non-steroidal anti-inflammatory agents can lead to the formation of additional pro-inflammatory derivatives of arachidonic acid produced through the 5-lipoxygenase pathway which play a role in immediate hypersensitivity reactions and also have pronounced inflammatory effects. Administration of the NSAIDs alone can produce allergic reactions including bronchospastic reactivity, skin rashes, syndrome of abdominal pain, fever, chills, nausea and vomiting, and anaphylaxis. For this reason, aspirin and the other non-steroidal anti-inflammatory agents (NSAIDs) are generally contraindicated for patients suffering from asthma or who have previously exhibited allergic sensitivity to aspirin or other NSAIDs. Co-administration of the 5-lipoxygenase inhibitors of this invention with cyclooxygenase inhibitors may mitigate the untoward side effects of the latter and allow the increased advantageous use of such cyclooxygenase inhibitors.
Prior to the recognition of the significance of the 5-lipoxygenase pathway of arachidonic acid metabolism in allergic reactions and inflammation, the search for effective therapeutic agents was based primarily on those agents which treated the symptoms of allergy and inflammation. There has since been an effort to develop new drugs which selectively block the formation of the mediators of these conditions, and the present invention provides hydroxyalkylthiophenols which are inhibitors of the 5-lipoxygenase pathway and are useful in the treatment of asthma, rheumatoid arthritis, psoriasis, and other allergy, hypersensitivity reactions, and inflammatory conditions.
To date, benoxaprofen has been the only commercial anti-inflammatory agent which has 5-lipoxygenase inhibition activity. Prior to its withdrawal from the market because of untoward side effects, benoxaprofen was considered to represent a significant advance in the treatment of crippling arthritis and psoriasis. Thus, there remains a longstanding need for agents which block the mechanisms responsible for inflammation and allergic reactions, and which can be safely employed to treat, for example, arthritis, asthma, psoriasis and other dermatoses, allergic reactions and other 5-lipoxygenase mediated conditions. A need also exists for agents which can be administered with the inhibitors of other lipoxygenase enzymes, e.g. cyclo-oxygenase, to mitigate their side effects and support their desirable medicinal properties.
See Bengt Samuesson, "Leukotrienes: Mediators of Immediate Hypersensitivity Reactions and Inflammation", Science, Vol. 220, pp. 568-575 (May 1983); Michael K. Bach, "Inhibitors of Leukotriene Synthesis and Action", The Leukotrienes, Chemistry and Biology, pp 163-194 (Academic Press, Inc., 1984); C. W. Lee et al., "Human Biology and Immunoreactivity of Leukotrienes", Advances in Inflammation Research, Volume 6, pp 219-225 (Raven Press, New York 1984); Editorial, "Leukotrienes and other Lipoxygenase Products in the Pathogenesis and Therapy of Psoriasis and Dermatoses", Arch. Dermatol, Vol. 119, pp 541-547 (July, 1983); Robert A. Lewis et al., "A Review of Recent Contributions on Biologically Active Products of Arachidonate Conversion", Int. J. Immunopharmac., Vol. 4, No. 2, pp 85-90 (1982); Michael K. Bach, Biochemical Pharmacology, Vol. 23, No. 4, pp 515-521 (1984); and E. L. Becker, Chemotactic Factors of Inflammation, pp 223-225 (Elsevier Science Publishers V.B., Amsterdam, 1983); Sharon, P. and Stenson, W. F., Gastroenterology, Vol. 84, 454 (1984); and Musch, M. W. et al., Science, Vol. 217, 1255 (1982).
The present invention provides compounds which block the 5-lipoxygenase metabolic pathway and, therefore, block the formation of the leukotrienes responsible for allergy and inflammation, and represent a new class of therapeutic agents which are useful in the treatment of allergic and hypersensitivity reactions and inflammation, alone, or also may be utilized in combination with cyclooxygenase inhibitors such as the non-steroidal anti-inflammatory agents.
B. Prior Art
Wagner et al. U.S. Pat. No. 4,029,812, and related U.S. Pat. Nos. 4,076,841 and 4,078,084 which issued from divisional applications of the -812 application, all assigned to the Dow Chemical Company, disclose 2-(3,5-di-tert-butyl-4-hydroxyphenyl)thiocarboxylic acids, esters and simple amides which are hypolipidemics and are useful in reducing plasma lipid levels, especially cholesterol and triglyceride levels.
The Wagner et al. and related compounds have also been reported in the literature as plasticizers and pesticides. See for example, Khim. Tekhnol. 20(4), 568-574 (1977); German Offenlegenschrift DE 2716125 (1977); Pestic. Biochem. Physiol. 1979, 12(1), 23-30.
Primary sulfide alcohols having hindered phenol groups have been reported in the literature as plasticizers, stabilizers, anti-oxidants and elastomers. See U.S. Pat. No. 4,108,831 which discloses hydroxyalkylthiophenols used as antioxidants to stabilize polymers against oxidative degradation; CA81(21:135705b; CA82(18):112655s; CA82(13):86191r; CA82(13):86190q; Eur. Pat. Appl. EP 60799 Al; and CA82(13):86196w.
Cottman, U.S. Pat. No. 4,108,831 discloses antioxidants for the stabilization of polymers and other materials subject to oxidative degradation which have the formula ##STR5## wherein R.sup.1 and R.sup.2 are selected from the group consisting of hydrogen and hydrocarbon radicals containing 1 to 12 carbon atoms, R.sup.3 is a monohydroxy or dihydroxy substituted radical containing 1 to 11 carbon atoms, at least one carbon atom of which is non-aromatic, more particularly a part of a non-cyclic (open chain) aliphatic radical. The non-aromatic portion of R.sup.3 contains the hydroxy substitution with the proviso that when R.sup.3 contains 2 hydroxy substituents the substituents are located on different carbon atoms, wherein n is 1 or 2 and wherein the thio radical is attached to the phenolic ring in a position ortho or para to the hydroxy group, with the further proviso that when n is 1, R.sup.3 is a saturated or unsaturated hydrocarbon radical and when n is 2, R.sup.3 is a saturated hydrocarbon radical which can contain 1 or 2 oxyether linkages, i.e. --O--.
A preferred embodiment includes those compounds wherein R.sup.1 and R.sup.2 are hydrogen or tertiary alkyl radicals having 4 to 9 carbon atoms and are located in the positions ortho to the hydroxy group, and wherein the thio group or groups are in positions para to the hydroxy groups, and wherein n is 1 and R.sup.3 has the structural formula ##STR6## wherein R.sup.4 is selected from the group consisting of hydrogen, methyl or phenyl and wherein n is 2 and R.sup.3 is the group ##STR7##